FAMILIAL HYPERINSULINEMIA DUE TO A STRUCTURALLY ABNORMAL INSULIN - DEFINITION OF AN EMERGING NEW CLINICAL SYNDROME
FAMILIAL HYPERINSULINEMIA DUE TO A STRUCTURALLY ABNORMAL INSULIN - DEFINITION OF AN EMERGING NEW CLINICAL SYNDROME
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DOI：
10.1056/nejm198405173102004
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发表时间：
1984-01-01
影响因子：
158.5
通讯作者：
RUBENSTEIN, AH
中科院分区：
文献类型：
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作者：
HANEDA, M;POLONSKY, KS;RUBENSTEIN, AH
一名患者被确诊为轻度糖尿病，明显的空腹高胰岛素血症(-130u.U胰岛素/毫升)，空腹C肽与胰岛素摩尔比降低至1.11至1.50(正常)。患者对外源性胰岛素反应正常。她的内源性免疫活性胰岛素在高血糖的葡萄糖钳制研究中显示出生物活性降低，并在体外与胰岛素受体结合和刺激葡萄糖运输的能力降低。家系研究显示，3代中的另外5名亲属有不同程度的糖耐量不耐受，显著的高胰岛素血症，外周血C肽与胰岛素摩尔比降低。从患者和高胰岛素血症家族成员的循环白细胞中提取的DNA的限制性内切酶裂解显示，胰岛素基因的一个等位基因中的MboII识别位点丢失-与胰岛素B链第24或25位的点突变一致。其他使用高压液相色谱和详细基因分析的研究证实，该缺陷是胰岛素B链第24位苯丙氨酸取代的丝氨酸。对于对外源性胰岛素反应正常且C-肽/胰岛素摩尔比降低的高胰岛素血症患者，应考虑结构异常胰岛素的分泌。糖耐量可能从相对正常到明显的糖尿病。
A patient was identified with mild diabetes, marked fasting hyperinsulinemia (89-130 .mu.U of insulin/ml), and a reduced fasting C-peptide: insulin molar ratio of 1.11 to 1.50 (normal, > 4). The patient responded normally to exogenous insulin. Her endogenous immunoreactive insulin showed reduced biologic activity during a glucose-clamp study with hyperglycemia and a reduced ability to bind to the insulin receptor and stimulate glucose transport in vitro. Family studies showed that 5 additional relatives in 3 generations had variable degrees of glucose intolerance, marked hyperinsulinemia, and a reduced peripheral C-peptide:insulin molar ratio. Restriction-endonuclease cleavage of DNA isolated from circulating leukocytes in the patient and in family members with hyperinsulinemia revealed loss of the MboII recognition site in one allele of the insulin gene - consistent with a point mutation at position 24 or 25 in the insulin B chain. Other studies using high-pressure liquid chromatography and detailed gene analysis identified the defect as a serine for Phe substitution at position 24 of the insulin B chain. The secretion of a structurally abnormal insulin should be considered in patients with hyperinsulinemia who respond normally to exogenous insulin and have a reduced C-peptide:insulin molar ratio. Glucose tolerance may range from relatively normal to overtly diabetic.